Rheumatoid arthritis and risk for Alzheimer’s disease: a systematic review and meta-analysis and a Mendelian Randomization study

Rheumatoid arthritis (RA) patients have been observed to be at a lower risk of developing Alzheimer’s Disease (AD). Clinical trials have showed no relationship between nonsteroidal anti-inflammatory drug (NSAID) use and AD. The aim of this study was to establish if there is a causal link between RA and AD. A systematic literature review on RA incidence and its link to AD was carried out according to the PRISMA guidelines. Eight case-control and two population-based studies were included in a random effects meta-analysis. The causal relationship between RA and AD was assessed using Mendelian Randomization (MR), using summary data from the largest RA and AD Genome Wide Association (GWA) and meta-analysis studies to date using a score of 62 RA risk SNPs (p < 5 * 10(−8)) as instrumental variable (IV). Meta-analysis of the literature showed that RA was associated with lower AD incidence (OR = 0.600, 95% CI 0.46–0.77, p = 1.03 * 10(−4)). On the contrary, MR analysis did not show any evidence of a causal association between RA and AD (OR = 1.012, 95% CI 0.98–1.04). Although there is epidemiological evidence for an association of RA with lower AD incidence, this association does not appear to be causal. Possible explanations for this discrepancy could include influence from confounding factors such as use of RA medication, selection bias and differential RA diagnosis.